We searched PubMed and Medline for all article types from January, 1957, to January, 2008. All languages were included. Search terms included “glucose”, “lipids”, “diabetes”, “vascular wall”, “atherosclerosis”, and “inflammation”. References were selected from journals on the basis of importance, novelty, and relevance. All article types were included. We gave priority to those that were published in the past 5 years in peer-reviewed journals.
ReviewCardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies
Introduction
Several mechanisms are likely to contribute to the accelerated atherosclerosis and increased cardiovascular disease risk noted in patients with type 2 diabetes mellitus. We focus on areas in which basic mechanistic studies have high relevance to present clinical controversies to understand and address cardiovascular disease risk in people with diabetes. We assess pathophysiological information linking hyperglycaemia, diabetic dyslipidaemia (other than the control of LDL cholesterol concentrations), and inflammation to the accelerated vascular injury and cardiovascular disease risk in type 2 diabetes and discuss clinical considerations.
Section snippets
Hyperglycaemia and the vessel wall
Although a consistent association between glycaemic control and cardiovascular disease has been noted in epidemiological studies,1 the effect of tight glycaemic control did not seem to reduce the cardiovascular risk in clinical trials.2 Intensive glycaemic control in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study3 was stopped because of an increase in the number of cardiovascular deaths. A formal analysis of the results has not yet been reported. The ADVANCE (Action in
Diabetic dyslipidaemia and the vessel wall
Diabetic dyslipidaemia is strongly related to atherosclerosis. Even though patients with type 2 diabetes might not have substantially increased concentrations of LDL-cholesterol compared with matched individuals without diabetes, a cornerstone of the management of cardiovascular disease risk in diabetes is the use of LDL-cholesterol-lowering drugs—ie, statins. These drugs generally reduce cardiovascular disease events by 25–50%40, 41 but the excess residual cardiovascular disease risk remains
Glycaemia versus hyperlipidaemia in pathogenesis of atherosclerosis
The roles of hyperglycaemia and hyperlipidaemia in atherogenesis have been difficult to separate in animal models of diabetes. Hyperlipidaemia is usually exacerbated by the onset of hyperglycaemia—eg, in mouse models of LDL-receptor deficiency and apolipoprotein-E deficiency—thereby confounding the effect of hyperglycaemia. However, in two animal models, hyperglycaemia seems to have an independent role.90, 91 First, fat-fed diabetic pigs had more atherosclerosis than equally dyslipidaemic
Chronic subclinical inflammation and the vessel wall
Evidence ranging from pathological studies in people to in-vivo mouse models has established the role of inflammatory cells (such as macrophages and T lymphocytes) and inflammatory mechanisms (such as cytokine release) in the pathogenesis of atherosclerosis.92 Because type 2 diabetes and atherosclerosis are chronic conditions that take decades to arise, the cause and effect are difficult to discern (figure 3). Inflammation is implicated in the pathogenesis of type 2 diabetes and atherosclerosis.
Conclusions
Data from in-vitro and animal model studies support the argument that the absence of intensive glycaemic control in the ACCORD trial3 should not eliminate hyperglycaemia as an important therapeutic target for reduction of cardiovascular disease in diabetes; the absence of effect might relate to an unfavourable benefit to risk ratio of the presently available glucose-lowering treatments in the patients recruited for that trial. In the ACCORD trial,3 the elderly at risk patients might have had
Search strategy and selection criteria
References (131)
- et al.
Short-term high glucose exposure induces monocyte-endothelial cells adhesion and transmigration by increasing VCAM-1 and MCP-1 expression in human aortic endothelial cells
Atherosclerosis
(2007) - et al.
Enhanced Cellular Oxidant Stress by the Interaction of Advanced Glycation End-Products with Their Receptors Binding-Proteins
J Biol Chem
(1994) - et al.
Susceptibility of low-density lipoprotein to oxidation and circulating cell adhesion molecules in young healthy adult offspring of parents with type 2 diabetes
Metabolism
(2004) - et al.
LDL oxidation is associated with increased blood hemoglobin A1c levels in diabetic patients
Clinica Chimica Acta
(2007) - et al.
Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis
Trends Pharmacol Sci
(2005) - et al.
Swings in blood glucose levels accelerate atherogenesis in apolipoprotein E-deficient mice
Biochem Biophys Res Comm
(2007) - et al.
Statins inhibit high glucose-mediated neutrophil-endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide
Microvasc Res
(2003) - et al.
Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: The distinct role of protein kinase C and mitochondrial. superoxide production
Atherosclerosis
(2005) - et al.
Increased uptake of alpha-hydroxy aldehyde-modified low density lipoprotein by macrophage scavenger receptors
J Lipid Res
(2000) - et al.
Scavenger receptors that recognize advanced glycation end products
Trends Cardiovasc Med
(2002)